Allopregnane compounds for topical application



United States Patent ALLOPREGNANE COMPOUNDS FOR TOPICAL APPLICATIONLewis H. sarettplrinceton, Nil, assignor to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey N0 Drawing. Filed Apr. 1 1955, Ser. No.498,753

6 Claims. (Cl. 167-58) This invention relates to therapeuticcompositions and particularly to such compositions containing as theeffective ingredient an allopregnane compound for topical applicationwhere cortisone therapy is indicated.

The topical application of hormones such as hydrocortisone and relatedcompounds has found widespread 'use in the treatment of topicalafllictions, such as dermatitis, acute sunburn, poison ivy, poison oak,eczema, atopic dermatitis, pruritus ani, pruritus vulvae, allergies andthe like. They have also produced favorable clinical response indiseases of the skin, such as neurodermatitis, lichens simplex,chronicus, seborrheic dermatitis and recunent vesicular dermatitis. Theeffect of such compounds on poison ivy, poison oak and similarafilictions has been startling, indicating that .these..scourges ofchildren and Weekend woodsmenwhich caused widespread suffering in thesummer can at last be eliminated or substantially reduced. Thisremarkable characteristic .has,'however, been substantiallylimited duetothe high systemic activity of the compounds. The danger of the activecompounds being absorbed into the system with the resulting hormoneunbalance has substantially limited the compounds potential widespreaduse.

i A primary object of the invention is to provide a therapeutictreatment for topical afilictions responding to cortisone therapyWithout the simultaneous introduction of harmful effects. A morespecific object is to provide a topical composition having a high orderof local activity. Other objects and the advantages of the inventionappear hereinafter. 1

These objects are attained, in general, by the use of a therapeuticcomposition comprising an intimate mixture of an allopregnane compoundwith a topical vehicle. This composition greatly extends theapplication'of hormone therapy to topicalafiiictions.

Theterm allopregnane compoundis meant to embrace those compounds havingthe structural formula:

CHR

wherein R is a divalent functional group, a monovalent functional groupand hydrogen, or two monovalent functional groups. These functionalgroups can be oxygen, hydrogen or alkoxy or acyloxy groups preferablyhaving a carbon chain length of from one to twelve carbon atoms,phosphate or its salts such as the alkali metal salts, or alkali metaland alkaline earth metal bisulfite addition .salts of the aldehyde. Thediscovery that these compounds have topical activity is surprising sincethey have u a completely saturated ring system. :Heretofore it was 02,943,978 Patented July .5, 1960 ice believed that one of the structuralfeatures of adrenal cortical steroids necessary for activity was adouble bond at the 4,5 position. Typical examples of such allopregnanecompounds are sodium salt of allopregnane-1lfl,l7a,21-triol-3,2l0-dione21-phosphate; and other alkali metal salts thereof; allopregnane-11 5,17a-dioI-BJO-dione 2l-al and alkali metal bisulfitederivatives thereof;allopregnane-l lB,17o,21,21-tetraol-3 ,ZO-dione;21,21-dimethoxy-allopregnane-1 1fi,17ecdi0l-3 ,20-dione;2l,21-diethoxy-allopregnane-1 1fl,170t-dlO1-3,20-d.l0116allopregnane-l15,17a,2l,2l-tetraol-3,20-dione 21,21-diacetate;

and allopregnane-l l5,170;,2l,21-tetraol-3,20dione 21,21-

dibutyrate.

By the term topical vehicle is meant a vehicle for topical applicationof such consistency that it may be readily applied to the skin, eyes,nose, mouth, teeth or respiratory tract. Examplesof the dermatologicalvehicles which can be employed are vehicles of the Water-solubleointment base type, suchaspolyethylene glycols; vehicles which act as.oils, such as the water-immiscible olive oil or petrolatum,Water-miscible oils, such as anhydrous wool fat, oil-.in wateremulsions, such as vanishing creams, water-in-oil emulsions, such ashydrous wool fat, pastes, such as a mixture of starch and petrolatum,collodions; vehicles which act as aqueous mixtures, such as aqueoussolutions, mixtures of zinc oxide and water, and jellies; and vehicleswhich act as powders, such as the hydrophilic powders of which starch isan example or hydrophobic powders, such as talc or zinc stearate.

The particle size of the allopregnane compound present in thesecompositions is desirably less than microns and preferably less than 35microns. Very satisfactory results are obtained when the particle sizeof the active ingredients'is 10 to 15 microns or less.

Although the concentration of the active ingredient can be varied withinwide limits it is preferred to employ the allopregnane compound in anamount of at least 0.01% of the composition, depending on the particulardermatologic vehicle and the use intended. Although there is no limit onthe concentration of the active ingredient from the standpoint oftreatment it is ordinarily considered unnecessarily wasteful of thevaluable steroid to prepare compositions having an excess of abouttenpercent by weight of the active ingredient in the composition. Thevehicles containing from about 0.1% to about 5% of the. allopregnanecompound are believed. to be particularly satisfactory.

The compositions of this invention can also contain, in addition to theallopregnane compound, other active ingredients, such as antibioticagents. Such compositions containing mixtures of allopregnane compoundsand an antibiotic agent are particularly useful in the treatmentofinflammatory diseases which are complicated by concurrent infection.Antibiotic agents which can be utilized in these compositionsinclude'penicillin, streptomycin, neomycin, aureomycin, terramycin, chloromycetin;polymycin, tetracyclin and 'sulfonamide's.

The antibiotic is preferably about 100 units to 100,000 units in eachdosage unit.

A particularly satisfactory soft white ointment for treating poison ivyand the like consists of approximately 0.5 of anfallopregnane compoundin an oily base. It is ordinarily prepared by adding a suspension of anallopregnane compound such as allopregnane-milk,

present in amounts of from 21-triol-3,20-dione 21-acetate to a mixtureof white wax and petrolatum. The ointment is preferably milled aftercompounding" to eliminate crystalline agglomerates' or lumps and toproduce a smooth white preparation. Milling the finished product in thismanner provides an ultima te means of reducing the particle size of theallopregnane to the desired range.

Other pharmaceutical carrier-scan be employed in preparing such topicalointments; for example, the active ingredient can be mixedwater-immiscible or watermiscible oils, suchas petrolatum, lanolin orother suitable oil bases.

In addition to the topical ointments described above, lotions designedfor application to the skin may be employed. These are convenientlyprepared by suspending the active material in a suitable aqueous vehiclecomprising mainly glycerol, alcohol, soap, and water. i

A further type of topical preparation is a cosmetically acceptablevanishing cream containing an allopregnane compound. Suitable bases forthis cream are typical oilin-water emulsions comprisinga soapemulsifying agent, free stearic acid and water to which other materials,such as, glycerin, mineral oil, cocoa butter, etc. are sometimes added.a I

, Still another type of preparation suitable for derma- Qtological useis a-dusting powder containing an allopregnane compound or one of itsderivatives as the active ingredient and talc or the like. 7 A'satisfactory ointment for treating inflammatory conditions of the skinaccompanied by the infections comprises approximately one to fiftymilligrams of an fallopregnanecompound and 500 to 10,000 units of anantibiotic in-an ointment base.- Examples of suitable 'bases' are liquidpetrolatum and white petrolatum, white Waxandthelikef It is currentmedical .and pharmaceutical practice to .standardize on preparationswhich contain uniform amounts of active ingredients; and, therefore,compositions for treating slain irritations and infections are preparedfor convenience containing /2 milligram, 1 milligram, -3 miligrams, 5milligrams, 10 milligrams and 15- q EXAMPLE Allopregnane-ll 8,17a,21triol-3,20-diorte 21 ac et ate Five grams of hydrocortisone acetate aresuspended in.

' 500 ml.,of benzene-methanol (9 to. 1), 5.0 grams of.5% palladiumbarium sulfate catalyst added, and themixj ture shaken at roomtemperature under hydrogen. The initialpressure is forty pounds Aftertwo hours hydrogen. absorption stops. The solvent is-filtered tom thecatalyst and concentrated to 100 ml. 300 ml. of ethanol is added andconcentration continues until crystalliza- .tion begins. After'cooling-afirst crop of 3.1 grams, melting point 210-213 C., [M +83;C. (acetone)ofallopregnane-llp, 17a,21-1Ii01-3,20-di0116 ZI-acetate is obtained. i 1V {f Allopregfiaue l1fi,17a,21-tri0l-3,20-di0ne.

1T0 8.8 grams ofallopregnane-11p,17e;,21-triol-3,20 dione ZI-acetatein400 ml. of methanol under nitrogen .iefitiqeili mlf Z N sod mimethoxide.;"I'he ture is stirred for fifteen minutes at roomtemperature, 4.1 ml. of glacial acetic acid added, and stirringcontinued five minutes longer. added and the whole concentrated toone-half volume. Another 300 m1. of water is added and again it isconcentrated to half volume giving crystals. After to 0 C. thecrystalline product is collected and recrystallized from acetone,melting point 227-235" C.

EXAMPLE 3 Allopregnane-J118,17a,21-triol-3,20-dione 21 t-butylacetate 1V One gram of hydrocortisone t-butylacetate in mL of benzene-methanol(10:1) is reduced under an forty pounds of hydrogen pressure in thepresence of 1.5 grams of 5% palladium supported on barium sulfate. Afterfour hours about one equivalent of hydrogen .is absorbed; the mixture isfiltered and concentrated to 25 ml. Addition of petroleum ether producescrystalline product which is recrystallized from benzene to givesubstantially pureallopregnane-l1B,17a,21-triol-3,20-dione .21-tertiarybutylacetate of melting point 245250 C. In a manner similar to thisother-21 esters can be prepared such as the propionate, benzoate,tricarbyllate, trimethylaceta-te, salicylate and palmitate.

EXAMPLE 4 Topical ointment of allopregnane-115,17a,21-tri0l- Y3,20-di0ne 21-acetate 7 Melt the carbowaxes and with stirring add thepropylene, glycol, zinc stearate and water. Pass the resulting ointmentthrough a roller mill using cold rollers until the ointment is smooth.The resulting ointment is es cially suited for dermatologic use.

EXAMPLE. 5

Topical ointment of allopregnane-115,1 702,2]:17'1'01- 3,20-di0neZI-terfim'y butylacetate Allopregnane-11p,17 ,21-trio1 3,20-dione21-,terti- Gm. ary butylacetate 0.010 Zinc stearate 0.078 Propyleneglycol 0.307 Carbowax 1500 0.380 Carbowax 4000 0.180 Distilled water0.045

Melt the carbowaxes and with stirring add the steroid, propylene glycol,zinc stearate and water. Pass the resulting ointment through a rollermill using cold rollers until the ointment is smooth. The resultingointment is especially suited for dermatologic use.

EXAMPLE 5 V Allopregnane-l 1,8,17u,21-trio1- 3,20-dione 21-acetat'e 6.0gm. v l f Bacitracin 8.0 gm. (400,000 units).

Liquid petrolatum 96.5 gm. White petrolatum 289.5 gm.

The liquid petrolatum and the white petrolatum are sterilized by heatingat C. for two hours. Approximately two-thirds of the liquid petrolatumand all of'tbe white petrolatum are then combined aseptically-in asterile Then 300 ml. of water container. 'The mixture'is heateduntilliquid, thoroughly mixed and then allowed to congeal. The 'allopregnaneand bacitracin aremixed and comminuted in a sterile mortar. Theremainder of the liquid petrolatum is then added to this mixture ofsolids and mixed well. The

previously prepared petrolatum base is then added in portions andthoroughly mixed to form a homogeneous mixture. The ointment remainsstable over an extended storage period and is especially suited forophthalmic use. I

EXAMPLE 7 The following ingredients are compounded in the same-manner'as-described in Example 6:

.Sodium bisulfite addition productof allopregnane-l 15,170:-

diol-3,20-dione'21-al 6.0 gm. Bacitracin 8.0 gm. (400,000 units).'Liquidpetrolatum 96.5 gm. White petrolatum 289.5 gm.

i The composition is useful as an ophthalmic ointment.

EXAMPLE 8 The following ingredients are -compounded in the,mannerdescrib'ed in Example 6 with the except-ion that .thevwhite waxis first combined with the major portion of petrolatum base: t

Allopregnane-l1B',17a;2l triol 3,20 dione 21- benzoate 60.00 Neomycinsulfate. 20.00 White wax 76.00 White petrolatum 2828.00 Liquidpetrolatum 1016.00

The composition is useful as an ophthalmic ointment.

EXAMPLE 9 The following ingredients are compounded in the sam mannerasdescribed in Example 8: I

A1lopregnane-11B,1'7cz,21 triol 3,20 -'dione 21- Gm.

stearate 60.00

' Tetracyclin 20.00 White wax 76.00

White petrolatum 2828.00

Liquid petrolatum 1016.00

The ointmentisparticularly suited for ophthalmic use.

' EXAMPLE 10 The following ingredients are compounded in the same manneras described in Example 8:

Sodium salt of allopregnane-llB,l7a,21-triol- Water to make 100.00 gm.

The non-ionic emplsifying wax, glyceryl monostearate, liquid petrolatumand anhydrous lanolin are melted at 70 C. and stirred together. Themethyl and N-propylp-hydroxybenzoatesare dissolved in 70% of the water,previously heated to 80 C. This aqueous solution is then added to themelted waxes with thorough stirring to form an emulsion. Theallopregnane is then milled together with the glycerol and 20% of thewater thus forming.a'thin slurry. Thisslurry is then added to thepreviously formed emulsion and thoroughly stirred'until the temperatureof the lotion base is about 35 C. The neomycin sulfate is dissolved in10% of the water (cool) and this solution is then added with stirring tothe. lotion base and the resulting mixture is homogenized.

EXAMPLE 12 An ointment is prepared having the following composition:

Bacitracin 2.0 gm. 100,000 units). Allopregnane 115,l7a,2l-triol-3.20-dione ZI-acetate 2.5 gm. White wax 4.0 gm. White petrolatum-to make100.0 gm.

The white wax and petrolatum are melted on a steam bath and the mixtureallowed to cool with stirringuntil it congeals. Thehydrocortisoneacetate and the bacitracin are incorporated by stirring in the coolbase. The mixture is then milledin-aroller mill until a uniform productis obtained. Themesultingointment is suitable for use in tneatin'g eyediseases.

' EXAMPLE 13 ointmentis preparedas-in Example 12' with the "exceptionthat 30mg. of terramycin hydrochloride per gram of ointment is used-inplace of the bacitracin.

' "EXAMPLE 14 An ointment is prepared as in Example 12 with theexception that 05mg. of tyrothricin per gram of ointment is 'used inplace'of the bacitracin.

EXAMPLE l5 An ointment is prepared as in Example 12 with theexceptiomthat 30 mg. of aureomycin hydrochloride'per gram of ointment'isused in'place of the bacitracin.

EXAMPLE 16 Anpointment is prepared as in Example 12 with the vexception'that 10,000-units of polymyxin B (as the sulfate): per"gram'of ointment is used in place of the bacitracin.

EXAMPLE 17 ointment is prepared as in Example 12 with the exceptionthat5 mg. of gramicidin per gram of ointment is .usedin place of bacitracin.

EXAMPLE l8 'Anointment is prepared as in Example 12 with the exceptionthat 3.5 mg. of neomycin sulfate per gram of ointment is used in placeof the bacitracin.

EXAMPLE 19 An ointment is prepared as in Example 12 with the exceptionthat 10,000 units of penicillin G potassium per gram of ointment is usedin place of bacitracin.

EXAMPLE 20 An ointment is prepared as in Example 12 with the exceptionthat 10 mg. of dihydrostreptomycin sulfate per gram of ointment is usedin place of the bacitracin.

active-component.

, XA L P Lu 1 ointment prepared as in Example 12' with the exceptin that10 mg; of; streptomycin sulfate perf gram of ointment is used inplace'ofjth b-acitracinl EX M E .2

An ointment is prepared'as in Ex-ample 121mm the 'exception that 1,000units of bacitracin' and 3.5 mg, of neomycin sulfate per'gram ofointment is used .the

ExaMrtEzs An ointment ispre'pared as the exception that 2 gm. ofd-4aminor 3-isoxazolidone in place of the bacitraoin. I v 1 A sterileophthalmic Suspension Mat as pi si g composition aseptically prepared:

Suspension: s T Allopregnane .-*1 1B 17a,2 1 ti iol 3 2 0-dionc.

21-acetate .-i fglllm 'Q ;;ing;; 25.0 Neomycin baser (presentas'fthefijsulfat'e), (sterile) i l g" 3.5 Sterilizedvehicle to makeLOcc. 1 Z Vehicle: f i f 1i Sodium chloride 111g" 4 -8 Sodium citrate.2H 0mg i 1.0 Sodium phosphatelH o; monobasic ..mg 4.5 phosphate,.anhydrous,-dibasi'c n1g 4.5 Carbowax 4000 mg.. 100.0 Tween 80 mg 0.2 Benzylkonium.chloride (12.8% solution) m 0.0016 Benzylalcnhnl "mg -..'*5.0

i V Distilled water tomalse 1.0 cc. 5 i

The vehicle is prepared by clissolving the components of the vehicle inthe water, clarified by filtration and sterilized by autoclavin g Thesterile allopregnane'is asepti-- 'ca11y suspended in a portion of thesterilized vehicle and milled until 90% of theparticles are belowmicrons in size. The sterile neomycin sulfate is aseptically dissolvedin a portion of the'sterilized vehicle and this solution addedaseptically to the cortisone suspension. After thorough agitation, thesuspension is aseptically diluted to volume with the sterilized vehicle.'1

EXAMPLE similar to Example 24 with the substitution of 25 mg. of

; allopregnane-l 1p,17u,21-triol-3,20-dione ZI-benZoate for theallopregnane 11fi,17a,21-tri01-3,20-di0ne Zi -acetate.

EXAMPLE 26 An ophthalmic suspension'is prepared in a manner 1 similar toExample 24 with the substitution of 12.5 mg.

of allopregnane-l1 9,17a,21-t1io1-3,20-dione v21-benzoate for 12.5 mg.of the allopreguane-l1fl,17a,21-triol-3,20-

dione ZI-acetate. Any departure from the above description whichconforms to the present invention is intended to be included within thescope of the claims.

-Wl1at is claimed is:

1. A therapeutic composition useful for the treatment of topicalafliictions that comprises an intimate mixture s of 0.01 to 10% byweight of an 'allopregnane compound in an oil, wherein R is selectedfromfthefclassconsisting of hydrogen and lower acyl radicals. p 2. Thetherapeutic composition of claim'i'l'gyvhere'in. theallopregnanecompound is =allopregnane .1.1pj,1 7n ,21-uiol-3,20-dione'21acetate? J 3."The therapeutic composition" off'c1aim"'1fw the allopregnane compound isallopregnanel'lfiflefiltrial-3,20-dione.

4. The therapeutic composition of claimn'l; wherein the allopregnanecompound'is allopregnane-11fi,17a,21- tniol-3,2 0-dionell-t-butylacet-at'ef i 5. A therapeutic composition useful'for' thetreatment --of topical afliictions that oomprises'an intimate mixture of0.01 to 10% by weight of an allopregnane compound havingtheformulai 12-;

in an oil-in-water emulsion, wherein is selected from the classconsisting of hydrogen and lower acyl radicals. 6. A therapeuticcomposition useful for the treatment "of topical afliictionsthatcomprises an intimate mixture I An ophthalmic suspension is preparedin a manner of 0.01 to 10% by weight of anallopregnane' compoundhavingtheformulaa i in a water-in-oil' emulsion, wherein R the class ofhydrogen and lower acyl References Cited 'in' the fileof thispateut 1 Il T D 'S a S A -EN'I I a -Murray Aug. 1 8, 1953 Gou1d Feb; 26', '1957OTHER REFERENCES 1 J. Biol.. Chem.,ivol; :195, 1952, :pp. ,7s 1 -7 s3;-,Pincus: The Hormones, vol. 1, 1948, Academy Press

1. A THERAPEUTIC COMPOSITION USEFUL FOR THE TREATMENT OF TOPICALAFFLICATIONS THAT COMPRISES AN INTIMATE MIXTURE OF 0.01 TO 10% BY WEIGHTOF AN ALLOPREGNANE COMPOUND HAVING THE FORMULA-